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© 2018 IJRAR November 2018, Volume 5, Issue 4 www.ijrar.org (E-ISSN 2348-1269, P- ISSN 2349-5138)

IJRAR1BKP063 International Journal of Research and Analytical Reviews (IJRAR) www.ijrar.org 412

Subdermal buprenorphine implant: Suitable

alternative in the management of opioid addiction Vandna Kalsi2, Barinderjit Kaur1*

1Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional

University, Phagwara, Punjab, India.

2Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional

University, Phagwara, Punjab, India.

*Department of Pharmaceutical Sciences, I. K. Gujral Punjab Technical University, Kapurthala, Punjab, India.

ABSTRACT

Drug addiction is a relapsing brain disorder that leads to continuous drug seeking and repeated use. Drugs belonging

to the category of opioids are more attributed to the addiction and abuse. Symptoms of opioid addiction include

glazed or blood shot eyes, abrupt weight changes, constricted or dilated pupils, lethargy and depression.

Buprenorphine, a partial μ-opioid receptors agonist, is considered one of the best medicament for opioid abuse and

addiction. It is a semi-synthetic compound derived from thebaine and is available in different dosage forms. For

decades, oral or intravenous buprenorphine along with other opioids (methadone, oxycodone), antagonists

(naloxone and naltrexone), and combinations of the both (buprenorphine/naloxone) reduce cravings and recover the

patients from opioid addiction by blocking opioid receptors. However, intravenous and oral preparations of

treatment have certain restrictions and challenges. Buprenorphine when used sublingually or intravenously, the

fluctuations in plasma concentrations were reported. Moreover, the illicit use and addiction due to buprenorphine is

well documented even if it is widely employed for the addictive disorders. Many patients on buprenorphine therapy

were misusing their prescribed drug intravenously, while, some other purchased buprenorphine from individuals

with prescription. All of these confrontations let to the development of buprenorphine implants with same

therapeutic effect but minimum abuse potential. Therefore, Probuphine, a subdermal beprenorphine implant, that

release the active medicament over six months with minimum fluctuations, was developed. The release of

buprenorphine from such subdermal implants is reasonably constant, avoiding blood plasma fluctuations, has least

abuse potential and fairly safe. Moreover, the effect of buprenorphine can be terminated rapidly by removal of this

implantable formulation, advantage over other formulations. Therefore, among all the formulations of

buprenorphine, subplants are mostly preferred as the need for daily supervision and fluctuations in plasma

concentrations can be minimized. In this review, various aspects of opioid addiction pharmacotherapy,

buprenorphine formulations along with limitations and Probuphine efficacy and safety during opioid addiction are

highlighted.

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Key words: Buprenorphine; Opioid addiction; Probuphine; Subdermal implants.

INTRODUCTION

Drug addiction to illicit or prescription drugs is a serious and continuously growing problem. Despite the harmful

consequences of drug addiction some drugs are continually prescribed globally. Drugs belonging to category of

opioids, some sedatives or stimulants are attributed more to the addiction and abuse. Some opioid are prescribed as

pain relievers (e.g. oxycodone and hydrocodone) are liable to produce euphoria and are mostly abused. However,

some sedative-antianxiety ( e.g. alprazolam and diazepam) and even stimulants used for attention deficit

hyperactivity disorder (ADHD) ( e.g. amphetamine) are also misused or self–treated for some medical problems, so

liable to abuse for improving performance or getting high (Milone, 2012). After prolonged use of these drugs the

body can also develop dependence. Moreover, opioid addiction is more eminent world-wide due to increased and

easy availability of prescription opioid (Lankenau et al., 2012). Opioid dependence can also cause withdrawal

symptoms, which make difficult to stop taking opioids. If these drugs are taken more than the prescribed amount of

opioids, sometimes results in death (Byrne et al., 2009). Therefore, new products or treatments are always

demanded to attenuate the increase in opioid overdose and addiction to prevent mortalities globally.

Epidemiology of opioid addiction

Opioid abuse and addiction currently affects nearly 20 million people world-wide. Since 1990s increase in the

incidence of opioid use disorder deaths reported due to opioid overdose. In one study at United States, it is reported

that more than 11 million individuals misused opioid drug medications (Manchikanti et al., 2005). In 2015, it was

estimated that around 5.1 million people (1.9% person) in United State used heroin. In 2016, more than 20,000

mortalities observed in United State, caused by misuse of prescription opioid and nearly 13,000 mortalities due to

heroin overdose (Volkow, 2014). Due to these reasons, opioid drug misuse or addiction has been considered a

national emergency in various countries in 2017 (Murthy, 2016).

Treatment options for opioid addiction

Effective medication is available for the treatment of opioid addiction. For decades, oral, sublingual and injectable

preparations have helped patients to reduce drug abuse capability. Administration of opioid agonistic drugs

(oxycodine, methadone and buprenorphine), opioid antagonists (naloxone and naltrexone), and combinations of the

both (buprenorphine/naloxone) have been proven beneficial for the patients to recover from opioid addiction

(Yokell et al., 2011). The two important WHO-approved medications for opiate maintenance therapy are

buprenorphine and methadone, also regarded as “essential medications. These have been chosen for long term

maintenance therapy as well as detoxification of addictive opioids (Mattick et al., 2003). Both drugs have unique

properties that determine their suitability for individual patient.




It is well known that until 2000, the drugs used for opiod use disorders were limited to only methadone and

naltrexone. Therefore, methadone and naltrexone, were prescribed mostly by qualified physicians. However, these

therapeutic options for treating opiate addicts were given only under some strict regulations (Manchikanti et al.,

2005; Mattick et al., 2003). Consequently, the Federal Drug Abuse Treatment Act, 2000, (DATA) explored a new

opportunity for opioid addicts by providing a certification for prescription of buprenorphine formulations by

attending a short-specialty training course. Only approved or certified physicians have been selected for prescribing

different buprenorphine or buprenorphine/naloxone preparations (suboxone, subutex) in established office-based

settings for managing addictive disorders. It has been found from diverse clinical studies that buprenorphine

maintenance therapy is as efficacious as the methadone therapy in reducing illicit opioid misuse or addiction

(Fudala and Woody, 2004).

Furthermore, first line and second line treatment strategies are employed for the management of opioid misuse and

addiction. In first line treatment, buprenorphine-naloxone combination is preferred whereas methadone is used as

second line drug therapy for opioid drug abuse and addiction. Opioid addiction treatment is initiated with

buprenorphine-naloxone because buprenorphine has multiple advantages over other drug treatments, including more

safety in terms of overdose risk and naloxone prevent abuse of this medication. Secondly, this combination not only

reduces the risk of adverse events and mortalities to a greater extent, but also facilitates safe take-home dosing

(Connock et al., 2007). However, opioid addiction treatment with methadone suggested only when buprenorphine-

naloxone combination does not give satisfactory results (Joseph et al., 2000).

Both buprenorphine and methadone are important in reducing withdrawal symptoms. Methadone acts on mu opioid

receptor. Methadone due to its longer elimination long half-life (24-36 hours) and slow onset of action, allows for

once daily dosing, making methadone an important effective tool in opioid addiction treatment (Stimmel and Kreek,

2000). However, recent studies indicated the association of methadone with some significant cardiac effects,

especially prolonged QT interval during ECG of patient on methadone medication (Stotts et al, 2009). In one study

on hospitalized-methadone maintained patients, approximate 16.2% of prolonged QT interval cases were observed

when compared with non-methadone therapy (Smith et al., 2008).

Therefore, establishing successful buprenorphine regimen is of utmost important because reduced mortality rates

were observed with buprenorphine when compared with methadone treatment.

Buprenorphine

Buprenorphine, a partial µ-opioid agonist, has been utilized successfully for managing opioid addiction in various

preparations including tablet, injections, sublingual films as well as subdermal implants (Rosenthal et al., 2017).

Due to its strong affinity for µ-opioid receptor, buprenorphine is reported to antagonize the reinforcing effect of

exogenously administered opioids.




Mechanism of action

Buprenorphine has strong affinity as agonist at µ- opioid receotor, whereas at κ- opioid recptors it acts as a full

antagonist. Owing to its strong affinity and limited intrinsic activity for µ-opioid receptors, it antagonizes the

reinforcing effect of exogenously administered opioids. Buprenorphine has reward enhancement properties on acute

basis which has been reported effective in reducing opioid craving and withdrawals during detoxification. The locus

for reward and feeling of well being mainly present in the meso-limbic system of nervous system. This reward

circuit in brain is controlled by various neurotransmitters including dopamine (DA) (Wee and Koob, 2010). DA

along with its varying neurochemical functions in brain has also been reported to produce some other important

effects such as euphoria and stress reduction. Therefore, release of dopamine and other chemicals into the nucleus

accumbens causes feelings of euphoria (Bruneau et al., 2018). Uses of opiods during abuse or addiction induce

dopamine release from synapses of nucleus accumbens. Indulgence in this habit may force the individual in “self-

medication” which provides short term relief from discomfort and a “pseudo feeling” of well being (Kosten and

George, 2002). Buprenorphine antagonizes the reinforcing effect of exogenously administered opioids by acting at

µ-opioid receptors.

Although, all above mentioned drugs are found to be successful, however, patients sometimes become addicted to

these agonists themselves, therefore, the risk of drug abuse/misuse or addiction has been increased. Consequently,

some another dosage forms of buprenorphine have been developed as a preferable method of drug delivery.

Buprenorphine formulation in opioid addiction

Buprenorphine currently available in market in various formulations such as sublingual tablets (Subutex, Zubsolv),

combination of buprenorphine with naloxone (suboxone), buprenorphine buccal film (Bunavail), injectable

buprenorphine injection (sublocade) and subdermal implants (probuphine) etc. (Walley et al., 2008; Harricharan and

Farah, 2017). Buprenorphine in the form of mono as well as combination product is long available as sublingual

medication in the form of tablet. However, soluble buprenorphine/naloxone in the form of film, for sublingual or

buccual use has also been developed (Manlandro, 2005). These films have advantage over tablets as these

preparations are not subjected to gastrointestinal enzyme and dissolved and absorbed more quickly through oral

mucosa, therefore, gastrointestinal adverse effects can be reduced. However, subdermal implants containing

buprenorphine offer more advantages over other formulations by maintaining stable blood plasma concentrations

and ensuring compliance. These implants have gained more popularity in terms of reducing opioid misuse and

sustained prolonged clinical stability when compared with low to moderate doses of transmucosal buprenorphine

products including subutex or suboxone sublingual tablets/films (Boone et al., 2004). The newest long acting

subdermal buprenorphine implant, to date, is Probuphine which has been known to deliver steady-state levels of

medicament over the course of six months.




Buprenorphine tablets

Subutex

Subutex, contains active ingredient buprenorphine, is a sublingual tablet and has been approved for opioid abuse or

dependence treatment, primarily used as induction phase treatment of opioid addiction (Donaher and Welsh, 2006).

It is available in two different strengths including 2 mg and 4 mg buprenorphine sublingual tablets. Subutex must be

prescribed as a part of complete treatment scheme including counseling and psychological support (Graham, 2014).

Moreover, it has also been prescribed as over-the-counter drug in case of chronic pain, for which other long term

opiates are not tolerated well (Donaher and Welsh, 2006). Buprenorphine, in sublingual tablet form, is associated

with some complications, such as drowsiness, constipation and headache. Moreover, the sublingual buprenorphine

has less bioavailability ranging from 30-50 percent of the intravenous dose when absorbed through oral mucosal

membranes.

Zubsolv

Zubsolv is another sublingual tablet, a combination of buprenorphinen-naloxone, has also been indicated for the

treatment of individuals with addictive opioid disorder. It was approved by FDA in 2015 for starting buprenorphine

maintenance therapy in opioid dependent patients (Berger et al., 2014). The drug available in Zubsolv tablet in the

doses of 1.4mg/ 0.36mg, 5.7mg/ 0.36mg and 11.4mg/ 2.9 mg. This new formulations provide more bioavailability

of buprenorphine than other dosage forms. Combined buprenorphine/naloxone medications has been preferred more

(except during pregnancy, lactation and naloxone allergy) than buprenorphine monotherapy, as it has been reported

to have less possibility of abuse and addiction (Gunderson and Sumner, 2016).

Buprenorphine, in Zubsolv, when given sublingually is fairly well absorbed, whereas naloxone is absorbed

insufficiently by the same route. Therefore, due to the lack of appreciable naloxone absorption by sublingual route

of this combined medicament, no specific adverse effects were observed (Strickland and Burson, 2018). However,

recommended target maintenance dose of Zubsolv is 11.4mg/ 2.9mg, administered as a single daily dose, therefore,

chances of patients non- compliance increased. Furthermore, buprenorphinen-naloxone combination diversion and

illict use have been widely documented in different geographical regions around the world (Harrison et al., 2018).

Injectables

Buprenex

Buprenex is an injectable buprenorphine hydrochloride preparation, administered via intravenous or intramuscular

route. It is mainly recommended in acute or sever pain conditions to reduce the pain and not solely for abuse

treatment (Rosenthal and Goradia, 2017). But in addiction management it has been reported to ease withdrawal

symptoms. However, wide range of adverse effects such as euphoria, confused behavior, dryness of moth, slurred

speech, blurred vision, fatigue, dry mouth, slurred speech, hypertension, tachyarrhythmia and constipation were




Sublocade

Further, injectable buprenorphine is widely employed for the management of opioid dependency, however, it’s

illegal use and addiction has been well documented. In one study it is reported that approximate 20% patients on

intravenous buprenorphine therapy were abusing their prescription (Longshore et al., 2005).

Buccul film

Bunavail

Bunavail, a buccal lining, consists of buprenorphine-naloxone combination in the ratio of 4:1.

Buprenorphine in bunavail, a partial µ-opioid agonist and naloxone, an opioid antagonist, are

available in the form of transmucosal buccal preparation. A bunavail buccul film, having 4.2mg/

0.7 mg medicament, provides comparable buprenorphine exposure when compared with

suboxone 8 mg/ 2 mg sublingual tablet (Rosenthal and Goradia, 2017).

found with this preparation. Furthermore, due to more chances of drug abuse and addiction, even at recommended

doses, it is reserved for individuals, for which alternative treatments are not available (Rosenthal and Goradia,

2017).

Sublocade, a monthly injection of buprenorphine only, is used to treat opioid abuse and addiction. It has been

approved by FDA on November, 2017 for managing the opioid addiction disorder in those patients who already

have initiated treatment with other form of buprenorphine like suboxone. The injection is given monthly with a

minimum of 26 days gap between treatments. Sublocade when injected

subcutaneously, it forms a solid mass under the skin and buprenorphine released slowly over the time, allows

constant concentration of buprenorphine to enter the blood. However, the patient’s plasma level needs to be

monitored carefully when patient is on sublocade therapy. One major benefit of Sublocade is that it needs to be

injected once a month only versus the other forms of buprenorphine those need to be taken daily (Rosenthal and

Goradia, 2017).

Bunavail has been administered daily in a single dose through buccal cavity. The buccal film sticks to mucosa upon

contact with moist oral mucosal membrane and dissolved slowly to provide its full effect. If two films of bunavail

are required for one dose, one film should be placed near the mucosa of one side of oral cavity, whereas other

film upon the mucosa of other side of oral cavity. If multiple doses of bunavail are required, then no more than

two films should be applied to mucosal membrane at the same time. Bunavail transmucosal films dissolved

completely after application. Therefore, if bunavail film is chewed or swallowed it can leads to lower peak

concentrations and lower bioavailability (Chan, 2016). However, as this drug required daily administeration the

chances of non- compliance increased.




Suboxone

Suboxone, a sublingual film (also available as sublingual tablet), is a prescription medicine that has been employed

for the treatment of addicted adults. This sublingual film consists of buprenorphine and naloxone as active

ingredients in the ratio of 4:1. Buprenorphine helps to alleviate the symptoms of opiates withdrawal, whereas

naloxone prevent abuse of this medication It is also consider somewhat more safer since suboxone is FDA-

approved drug for both phases of treatment including induction as well as maintenance phase during opioid abuse

and addiction treatment (Kress, 2009; Velander, 2018). Moreover, this drug combination has been reported to

prevent parentral abuse due to the presence of naloxone.

All above mentioned treatment strategies requires frequent visits to clinics or hospitals for supervision of dosing,

which not only reduce the patient independence, but also incure significant staff time and cost (Byrne and Wodak,

2007). Therefore, various constrains of well established buprenorphine formulations have increased interest in the

development of subdermal implants as the alternative options (Lanier et al., 2008).

Subdermal implant

Probuphine

Probuphine a newest buprenorphine implant has been approved by FDA in 2016 for the use in patients aged 16-65

years. Probuphine is a subdermal implant containing buprenorphine equivalent to 80 mg and consist of four small

devices, implanted surgically under the skin of patient’s upper arm and removed after sixth months. The dose of

buprenorphine in Probuphine is fairly released at a constant and measured rate for six months as well as stabilize the

drug levels in the blood, therefore, this preparation has improved patient compliance, adherence to treatment and

comparable safety (Smith et al., 2017).

This implant offers advantages on other formulations as its long term delivery formulation maintain stable plasma

concentrations of drug, ensuring compliance and reduce the likelihood of abuse and diversion. Various studies

reported that the depot of buprenorphine base in different oils like sesame oil or oleaginous vehicles (e.g. castor oil,

cottonseed oil, peanut oil and soybean oil) produced a dose-related long-lasting effect (Lopatko et al, 2003).

Secondly, this implant helps to circumvent accidental toxicity of patients due to ingestion of tablet form of

medicament. Another advantage is that it can be placed in out- patient settings, thus avoiding the stressful

environment of hospital stay (Barnwal et al., 2017).

The most common adverse reactions associated with Probuphine are due to their insertion and removal techniques

and include pain, severe itching and haematoma at the implant site. The minor adverse events associated with this

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medicine are headache, constipation and insomnia mainly due to the active substance buprenorphine (Itzo and

Guarnieri, 2017).

Therefore, buprenorphine subdermal implant, Probuphine has been approved for opioid misuse disorders and only

product of buprenorphine in the market that provides non-fluctuating blood levels of buprenorphine continuously

for at least six months after a single implant procedure.

Conclusion

Opioid addiction is a chronic disorder that requires a long-term treatment approach. Many treatment strategies for

reducing the risk of opioid misuse and addiction have been developed but every treatment has different adverse

effects on body. In market, the drugs available for treating opioid dependence are methadone, naltrexone, naloxone

and buprenophine. At one time methadone was considered as one of the gold standard drug for the treatment of

opiates misuse, however, recently it is mentioned that buprenorphine formulations are more effective with minimum

adverse effects. Among various buprenorphine preparations, Probuphine subdermal implant is considered best

medication for treating opioid addiction because it does not produce severe side effects as well as not required for

frequent dosing. This review mainly focused on Probuphine because this subdermal implant maintains the blood

level of buprenorphine for six month with no withdrawal symptoms and is likely to reduce the amount of illicit

diversion. Furthermore Probuphine implant require only semiannual administration, therefore reduce the need of

take-home doses and minimize the risk for potential nonadherance and abuse. In conclusion, awareness should be

created among the population regarding the harmful effect of opioid addiction and best treatment options including

subdermal implants employed at right time by organizing medical health camps.

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